Summary of the invention
The present invention is according to my chemosynthesis experience for many years, in conjunction with modern medical equipment technology, provides a kind of specific substitution value, and anti-microbial activity is strong, and good stability acts on good chitosan quaternary ammonium salt microspheres product.
Invention embodiment is as follows:
Get 10 parts of epoxy chloropropane, 13 parts of trimethylamine hydrochlorides, put in reactor, add 40 parts of 30% sodium hydroxide solutions, stir 2 hours, make 2,3-epoxypropyltrimethylchloride chloride solution, get 8 parts of chitosans, put in ultrasonic reaction still, add 40 parts of Virahols, 30% 30 parts of sodium hydroxide solutions, 5 parts, sodium-chlor, 1 part, aluminum chloride, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds 100 parts of dehydrated alcohols, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add 120 parts of pure water, 15 parts, sea bath acid sodium, select ultrasonic frequency 40kHz, react 2 hours, spraying is dry, obtain chitosan quaternary ammonium salt microballoon.
The raw material standards that above-mentioned embodiment is mentioned is as follows:
Epoxy chloropropane: No. CAS: 106-89-8;
Trimethylamine hydrochloride: No. CAS: 593-81-7;
Sodium hydroxide: Chinese Pharmacopoeia version two ministerial standards in 2010;
Chitosan: No. CAS: 9012-76-4;
Virahol: Chinese Pharmacopoeia version two ministerial standards in 2010;
Sodium-chlor: Chinese Pharmacopoeia version two ministerial standards in 2010;
Aluminum chloride: Chinese Pharmacopoeia version two ministerial standards in 2010;
Hydrochloric acid: Chinese Pharmacopoeia version two ministerial standards in 2010;
Dehydrated alcohol: Chinese Pharmacopoeia version two ministerial standards in 2010;
Sea bath acid sodium: Chinese Pharmacopoeia version two ministerial standards in 2010;
The present invention starting material Jun Kecong used pharmaceuticals buys and obtains, as long as meet national standard, all can be used to implement the present invention program.
The key equipment that foregoing invention embodiment is mentioned is as follows:
Ultrasonic reaction still: ultrasonic frequency 10～40KHz;
(typical production producer: Nanjing Xian Ou instrument manufacturing company limited)
Above equipment Market all has sale, is not limited to listed typical production producer, as long as technical indicator can reach requirement, all can be used to realize the present invention.
" part " described in foregoing invention scheme refers to weight part.
While not indicating temperature of reaction and pressure in foregoing invention scheme, all refer to normal temperature, normal pressure.
In foregoing invention scheme, term used is pharmacy proprietary term, if no special instructions, all defers to Chinese Pharmacopoeia and State Food and Drug Administration's related specifications.
Four embodiments
Specific embodiments of the invention 1
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, spraying is dry, obtain chitosan quaternary ammonium salt microballoon.
Specific embodiments of the invention 2
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, add pure water 1000kg, stir 1 hour, pour in jetmizer, make the biological long acting antibiotic liquid of chitosan quaternary ammonium salt nasal cavity cleaning.
Specific embodiments of the invention 3
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, add pure water 1000kg, stir 1 hour, pour in pivoted arm atomizer, make the biological long acting antibiotic liquid of chitosan quaternary ammonium salt dentilave.
Specific embodiments of the invention 4
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, add pure water 1000kg, stir 1 hour, pour in spiral cover bottle for handling liquid toilet or cosmetic substance, make the biological long acting antibiotic liquid of chitosan quaternary ammonium salt vagina lavation.
Specific embodiments of the invention 5
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, add pure water 7kg, stir 1 hour, pour in vaginal jellies feeder, make the biological long acting antibiotic gel of chitosan quaternary ammonium salt vaginal plugging.
Specific embodiments of the invention 6
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, add pure water 7kg, stir 1 hour, pour in anus gel feeder, make the biological long acting antibiotic gel of chitosan quaternary ammonium salt hemorrhoid.
Specific embodiments of the invention 7
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, add pure water 1000kg, stir 1 hour, pour in transverse jet day with fog, make biological long acting antibiotic liquid liquid for chitosan quaternary ammonium salt skin.
Specific embodiments of the invention 8
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, add pure water 1000kg, stir 1 hour, pour in spray bottle, make the biological long acting antibiotic liquid of chitosan quaternary ammonium salt.
Specific embodiments of the invention 9
Get epoxy chloropropane 100g, trimethylamine hydrochloride 130g, puts in reactor, adds 30% sodium hydroxide solution 400g, stirs 2 hours, makes 2,3-epoxypropyltrimethylchloride chloride solution, get chitosan 80g, put in ultrasonic reaction still, add Virahol 400g, 30% sodium hydroxide solution 300g, sodium-chlor 50g, aluminum chloride 10g, stir 1 hour, add 2, 3-epoxypropyltrimethylchloride chloride solution, select ultrasonic frequency 37kHz, be warming up to 78 ℃, react 3 hours, add 10% hydrochloric acid adjust pH to 7.0, suction filtration, filter cake adds dehydrated alcohol 1000g, stir 2 hours, suction filtration, filter cake is put in ultrasonic reaction still, add water 1200g, sea bath acid sodium 150g, select ultrasonic frequency 40kHz, react 2 hours, add pure water 100kg, stir 1 hour, pour in spiral cover bottle for handling liquid toilet or cosmetic substance, make the biological long acting antibiotic liquid of chitosan quaternary ammonium salt cleansing enema.
With embodiment, investigate actual effect of the present invention below:
(1) the chitosan quaternary ammonium salt microballoon substitution value that embodiment 1 makes is measured.
1 measuring method
According to potentiometry (appendix VII A of Chinese Pharmacopoeia version in 2010), measure, get embodiment 1 sample 0.1g, accurately weighed, put in Erlenmeyer flask, add 100ml deionized water, with the AgNO3 titrating solution titration of 0.017mol/L, meter record AgNO3 consumes volume, calculates chitosan quaternary ammonium salt substitution value.
Table 1 chitosan quaternary ammonium salt substitution value
| Name of product | Substitution value |
| The chitosan quaternary ammonium salt of embodiment 1 preparation | 0.93 |
Above data presentation: chitosan quaternary ammonium salt microballoon prepared by the present invention has specific substitution value 0.93.
(2) the chitosan quaternary ammonium salt microballoon bacteriostatic activity that embodiment 1 makes.
The contrast of table 2 chitosan quaternary ammonium salt bacteriostatic activity
Above data presentation: the chitosan quaternary ammonium salt bacteriostatic activity that chitosan quaternary ammonium salt microballoon prepared by the present invention is prepared than prior art significantly strengthens, p < 0.01.
(3) the chitosan quaternary ammonium salt polymeric microspheres stabilize that embodiment 1 makes.
The chitosan quaternary ammonium salt validity period contrast table that table 3 embodiment 1 makes
Above data presentation: the chitosan quaternary ammonium salt-stable that chitosan quaternary ammonium salt microballoon prepared by the present invention is prepared than prior art significantly strengthens, p < 0.01.
(4) the biological long acting antibiotic gelation time of chitosan quaternary ammonium salt hemorrhoid that embodiment 6 makes
Table 4 contrast action time
Above data presentation: chitosan quaternary ammonium salt significant prolongation action time that the biological long acting antibiotic gel of chitosan quaternary ammonium salt hemorrhoid prepared by the present invention is prepared than prior art, p < 0.01.
(5) the biological long acting antibiotic gel of the chitosan quaternary ammonium salt hemorrhoid clinical observation on the therapeutic effect that embodiment 6 makes
1 case situation
Statistics outpatient service and inpatient, observe hemorrhoid patients 60 examples, 34 years old mean age altogether.Patient has anus in various degree swollen red, has blood in stool, and severe pain symptom, clinical diagnosis is hemorrhoid.Patient is divided into two groups at random, and test group is taken the biological long acting antibiotic gel of chitosan quaternary ammonium salt hemorrhoid that embodiment 6 makes, and control group is taken commercially available MAYINGLONGZHICHUANGGAO.
2 efficacy assessment standards
Cure: symptom, sign disappear or substantially disappear, and integration reduces >=95%.
Effective: symptom, sign are obviously improved, integration reduces >=70%.
Effective: symptom, sign all take a favorable turn, integration reduces >=30%.
Invalid: symptom, sign are all not improved or increase the weight of, integration reduces < 30%.
Calculation formula: [integration before (the rear integration of integration-treatment before treatment) ÷ treatment] * 100%.
3 clinical observation result
The biological long acting antibiotic gel of the chitosan quaternary ammonium salt hemorrhoid clinical efficacy contrast table of table 5 embodiment 6 preparations
Above data presentation: the biological long acting antibiotic gel of chitosan quaternary ammonium salt hemorrhoid prepared by the present invention is evident in efficacy higher than commercially available MAYINGLONGZHICHUANGGAO, p < 0.01.
(6) the biological long acting antibiotic gel of the chitosan quaternary ammonium salt vaginal plugging clinical observation on the therapeutic effect that embodiment 5 makes
1 case situation
Statistics outpatient service and inpatient, observe vaginitis patient 82 examples, 29 years old mean age altogether.Patient has the symptoms such as pruritus of vagina in various degree, leucorrhea abnormal, private parts peculiar smell, and clinical diagnosis is vaginitis.Patient is divided into two groups at random, and test group is taken the biological long acting antibiotic gel of chitosan quaternary ammonium salt vaginal plugging that embodiment 5 makes, and control group is taken chitosan quaternary ammonium salt vaginal jellies prepared by prior art.
2 efficacy assessment standards
Cure: symptom, sign disappear or substantially disappear, and integration reduces >=95%.
Effective: symptom, sign are obviously improved, integration reduces >=70%.
Effective: symptom, sign all take a favorable turn, integration reduces >=30%.
Invalid: symptom, sign are all not improved or increase the weight of, integration reduces < 30%.
Calculation formula: [integration before (the rear integration of integration-treatment before treatment) ÷ treatment] * 100%.
3 clinical observation result
The biological long acting antibiotic gel of table 6 embodiment 5 chitosan quaternary ammonium salt vaginal pluggings clinical efficacy contrast table
Above data presentation: the biological long acting antibiotic gel gel of the chitosan quaternary ammonium salt vaginal plugging vaginal jellies of preparing higher than prior art evident in efficacy prepared by the present invention, p < 0.01.